Earnings Call Transcript - FULC Q2 2021

Operator, Operator

Good morning, and welcome to the Fulcrum Therapeutics Conference Call. Currently all participants are in listen-only mode. There will be a question-and-answer session at the end of this call. I would now like to turn the call over to Ms. Christi Waarich, Director of Investor Relations and Corporate Communications for Fulcrum. Ma'am please proceed.

Christi Waarich, Director of Investor Relations and Corporate Communications

Thank you, operator. Good morning. And welcome to the Fulcrum Therapeutics conference call. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business. With me on today's call are Bryan Stuart, President and Chief Executive Officer; Chris Moxham, Chief Scientific Officer; and Chris Morabito, Chief Medical Officer. Let me quickly run through this morning's agenda. Given today's news, we're going to focus our call on the FTX-6058 phase one healthy adult volunteer results. Bryan will begin a call with a corporate overview and key updates from the quarter. Chris Moxham will provide a review of the FTX-6058 deep preclinical data, Chris Morabito will review the clinical results and next programs, and Bryan will open the call for Q&A. With that, it's my pleasure to turn the call over to Bryan. Bryan.

Bryan Stuart, President and CEO

Thank you, Christi. Good morning, everyone. And thank you for joining us today. This past quarter was particularly notable for the significant progress in both of our clinical stage programs. In June, we announced positive results from the phase 2b ReDUX4 trial, where we were able to show that losmapimod slows disease progression and improves function in patients with FSHD, a severe and progressive form of muscular dystrophy that currently has no approved treatments available. These results strongly support our belief that losmapimod has the potential to be a safe and effective therapy for FSHD patients. With these promising data from ReDUX4 in hand, we plan to meet with the FDA in the second half of 2021 to discuss potential next steps. Moving to FTX-6058 today, we are very pleased to report compelling results from our ongoing phase one trial in healthy adult volunteers. As many of you know, the current treatment landscape for sickle cell disease includes therapies that target only select symptoms. The introduction of an oral therapy that can successfully target the root cause of sickle cell disease would represent a major advancement. We are especially excited about the results from this trial, both in terms of tolerability as well as the impact we see in the induction of fetal hemoglobin mRNA and an increase in fetal hemoglobin production. In this trial, we saw an impressive 4.5-fold induction of fetal hemoglobin mRNA. We also saw a 4.2-fold increase in fetal hemoglobin production, which indicates fetal hemoglobin expression. And we achieved maximal target engagement. Building on our extensive preclinical research, these results demonstrate proof of biology and mechanism. We're also pleased to share that FTX-6058 has been generally well tolerated to date, and the pharmacokinetics support once-daily oral administration. Encouragingly, these results provide the first evidence that FTX-6058 may be able to achieve or exceed the two to three-fold HbF induction we observed preclinically. This two to three-fold HbF induction threshold would not only be superior to hydroxyurea, the current standard of care, but is also predicted to provide meaningful clinical benefit to sickle cell patients. With these results in hand, we remain on track to initiate a phase 1B trial in sickle cell patients by the end of the year and plan to initiate a clinical trial in non-sickle cell hemoglobinopathies in 2022. I will note that both of our development programs came from our Fulcrum Seek discovery platform, which is a powerful and differentiated approach to drug target identification and the innovation backbone of our company that has allowed us to rapidly identify novel high-quality targets that modulate the root cause of genetically defined rare diseases. By enabling drug discovery at unprecedented scale in disease relevant settings, Fulcrum Seek creates an unparalleled opportunity to efficiently grow our pipeline. We expect the work we are doing at Fulcrum Seek will enable us to submit two new INDs by the first quarter of 2023. In addition, Fulcrum Seek has also enabled our ongoing collaborations with both Acceleron and Myocardium, which continues to proceed well. As you can see, we continue to make important progress across our clinical development programs, research collaborations, and discovery platform. With a cash runway that takes us into the first quarter of 2023, we expect to have meaningful updates from multiple key initiatives in the near term. With that, I'll turn the call over to Chris Moxham to speak more about our preclinical work with FTX-6058.

Chris Moxham, Chief Scientific Officer

Thanks, Bryan. Sickle cell disease is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. It is the most common type of inherited hemoglobinopathy and affects an estimated 100,000 people in the United States and millions more worldwide. In healthy individuals, red blood cells are round and biconcave, enabling efficient circulation through small blood vessels to carry oxygen to all parts of the body. In individuals with sickle cell disease, the red blood cells take on a characteristic sickle shape. Sickle cells often die prematurely, a phenomenon known as hemolysis, which causes a constant shortage of red blood cells or anemia. Also, when sickle red blood cells travel through blood vessels, they can become stuck, restricting normal blood flow. This can lead to a vaso-occlusive crisis or VOC. Beyond anemia and VOCs, people living with sickle cell disease typically suffer from other serious morbidities such as stroke and acute chest syndrome. Together, these complications significantly impact lifespan. Current therapies are unable to address the broad symptomatology of sickle cell disease and thus underscore the tremendous unmet need that remains in this diverse population. The therapeutic rationale for Fulcrum is to induce fetal hemoglobin or HbF. Human genetics clearly show that this mechanism can treat the root cause of the disease. People who carry the sickle cell mutation, as well as additional mutations that promote hereditary persistence of fetal hemoglobin, present with HbF levels that are often elevated above 20% and are associated with asymptomatic disease. These observations suggest that novel therapies that can achieve similar levels have the potential to provide a functional cure. I'd also like to point out that individuals with sickle cell disease typically have baseline HbF levels between 5% and 10% of total hemoglobin. This implies that an effective HbF inducer can provide meaningful clinical benefits by increasing HbF levels two- to three-fold above baseline. It has been shown, both clinically and genetically, that such levels of HbF can have a transformative impact for patients, including progressively reduced mortality, reduced recurring pain crisis events, and an increased likelihood of asymptomatic presentation. Using our Fulcrum Seek drug discovery platform, we identified EED as a biological target capable of robust HbF induction. EED is a non-catalytic subunit of the PRC2 complex. PRC2 propagates histone trimethylation, an epigenetic mark associated with decreasing HBB mRNA and HbF protein expression. We developed FTX-6058 as a highly potent oral small molecule EED inhibitor, capable of decreasing histone trimethylation levels through PRC2 inhibition, thereby inducing HBB mRNA and HbF protein expression in red blood cells. FTX-6058 has outstanding drug-like properties, and in addition to its potent EED binding and inhibition of PRC2, it has a highly selective and clean off-target profile. We were also issued a composition of matter patent that provides protection until 2034. We have profiled 6058 across numerous in vitro and in vivo preclinical models. In both healthy and sickle cell disease models, we observe a consistent two- to three-fold induction of HbF protein, and we observed strong correlations between mRNA and protein expression. As seen on the right, we are showing mRNA and HbF protein changes from healthy CD-34 positive cells and the Townes mouse model that highlight this consistent two- to three-fold correlation of mRNA and protein. The connectivity of concentration dependent increases in target engagement with the induction of HBB mRNA and HbF protein expression is a very consistent finding we have observed throughout the preclinical data set we've generated to date. In preclinical studies, the inhibition of EED with FTX-6058 also results in similar levels of HbF induction as compared to those reported with gene editing. Specifically, in erythroid cells derived from CD34 positive cells, FTX-6058 achieves a maximum of three-fold HbF induction in healthy and sickle cell donors. This is similar to published data from Vertex and CRISPR Therapeutics, demonstrating approximately three-fold HbF induction in CD34 positive cells from healthy donors by CTX-001, a BCL-11A gene editing approach now being studied in a phase 1, 2 clinical trial. On the left side of this slide, you can see we've profiled CD34 positive cells obtained from healthy and sickle cell donors or a donor with the sickle cell trait. In all cases, we observed a robust increase in the amount of HbF in response to treatment with FTX-6058. We see the characteristic two- to three-fold increase above baseline, equating to absolute HbF increases between 8% and 25%. If these post-treatment values were to translate into the clinic, FTX-6058 has the potential to provide meaningful benefit and even potentially curative levels of HbF administered as a once-daily oral pill. Considering the value proposition of an oral small molecule that can induce HbF levels two to three-fold, we believe it could be the preferred treatment option for patients, providers, and payers. As I mentioned, baseline HbF levels in sickle cell disease patients are typically 5% to 10%. Based on a strong body of literature generated to date, inducing HbF can address the root cause of sickle cell disease. In contrast with symptomatic treatments or stem cell transplant regimens used in conjunction with gene editing, an effective oral small molecule HbF inducer like FTX-6058 has the potential to be disease-modifying, addressing sickle cell disease pathology and symptomatology. Coupled with the potential for broad therapeutic benefit through convenient oral administration and distribution at scale to meet the medical need of a global patient population, we believe FTX-6058 may truly transform the treatment landscape. In our phase one healthy volunteer trial, we've included exploratory measures of HBB mRNA in response to treatment. One of the key reasons we're quantifying these measures is that erythropoiesis greatly influences total mRNA and protein levels as human stem cells in the bone marrow differentiate and eventually enter circulation as mature red blood cells. The proposed site of action for FTX-6058 is on the human stem cells in the bone marrow. As you can see, these newly exposed cells will take approximately two weeks to differentiate into reticulocytes and enter circulation from which we are sampling. This provides a narrow window of time to measure any HBB mRNA changes occurring in the context of this 14-day study. Thus, we developed a highly sensitive and robust droplet digital PCR assay to quantify HBB mRNA. Additionally, we utilized reticulocyte measurements that rely on specific immuno-detection of HbF to quantify any early change in HbF protein. Before turning the call over to Chris Morabito, I'd like to thank the team at Fulcrum, who have been working so hard on this program, and the volunteers who participated in this trial. It's a fantastic example of innovative drug discovery that has the potential to make a real impact on people living with sickle cell disease. Chris?

Chris Morabito, Chief Medical Officer

Thanks, Chris. I'd like to take a moment to remind everyone that the results we will be sharing are from our ongoing phase one clinical trial in healthy volunteers. As a reminder, the aim of this ongoing phase 1 trial is to evaluate safety, tolerability, and pharmacokinetics of FTX-6058 treatment. The trial is also collecting pharmacodynamic data to assess target engagement, HBB mRNA levels, and increases in reticulocyte counts, which are reticulocytes that contain HbF protein. Here you can see the design of the trial and the doses being studied in the single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. We've also included the expected target engagement and pharmacodynamic effect thresholds derived from PK/PD modeling of preclinical data. Based on this modeling, we expect that target engagement and pharmacodynamic effects will be observed in the 6, 10, and 20 mg MAD cohorts. To date, we have completed SAD cohorts 1 through 6 and MAD cohorts 1 through 3. FTX-6058 was generally well tolerated in all the SAD and MAD cohorts completed. There were no serious adverse events and no discontinuations. All treatment-emergent adverse events deemed at least possibly related to FTX-6058 were mild in both the SAD and MAD cohorts. There was one grade 4 event in the 10 mg cohort that was determined to be unrelated to the study drug. These tolerability and safety data are consistent with expectations and support advancing this trial. FTX-6058's pharmacokinetics profiles demonstrated dose proportionality across the SAD and MAD cohorts. The mean half-life is approximately six to seven hours, which was longer than what we originally modeled. This resulted in greater exposures at lower doses, which we believe directly influences the target engagement and pharmacodynamic effects observed at lower doses. Next, we will share the results from the three exploratory endpoints measured in our phase one trial. Shown on this slide as target engagement data demonstrating potent and robust inhibition of histone trimethylation, the key epigenetic mark facilitated directly by PRC2. We collected samples at baseline, denoted as T-1. We then collected samples to measure target engagement at days 7 and 14 during treatment, including at the safety follow-up visit denoted by SFU, which occurred 7 to 10 days after the last dose at day 14. These results demonstrate that maximal target engagement was achieved by day 7 in the 6 and 10 mg cohorts, and at 20 mg after 14 consecutive days of treatment. Notably, subjects retained about 20% of baseline histone trimethylation levels at maximal target engagement, consistent with the preclinical data we've generated. Overall, these clinical results demonstrate that FTX-6058 is a potent inhibitor of PRC2 activity. Next, we will share the HbF mRNA clinical data. FTX-6058 treatment resulted in both time and dose-dependent increases in HbF mRNA, demonstrating proof of biology. Here we're presenting these pharmacodynamic effects in data from the 2 mg, 6 mg, and 10 mg MAD cohorts, plotted as fold induction over placebo at each time point. There is clear evidence of dose proportionality. At 2 mg, there is evidence of HbF mRNA induction; however, the changes at days 7 and 14 are not statistically significant. In both the 6 and 10 mg cohorts, we observed statistically significant HbF mRNA induction, with the 10 mg cohort achieving a mean 4.5-fold induction after 14 days. You can see we're getting up to a maximum of 8-fold induction in the 10 mg cohort as indicated by the 95% confidence interval range. Encouragingly, all results presented in the 6 and 10 mg cohorts demonstrate statistically significant changes from baseline. I'll also point out that the HbF mRNA induction response is highly durable. A follow-up at 7 to 10 days after the treatment period showed that subjects maintained the HbF mRNA induction observed at day 14, which we believe will translate to HbF protein expression as well. This durability is also consistent with what we've demonstrated preclinically in the Townes mouse model. Before we move on, I want to contextualize the mean 4.5-fold HbF mRNA induction. I remind you that we observed a two- to three-fold induction of mRNA across multiple models preclinically, suggesting that these results are meeting and potentially exceeding the induction thresholds predicted to provide meaningful clinical benefit for sickle cell patients. I also note that preclinically, HbF mRNA induction was strongly correlated with HbF protein induction. Lastly, we will present the F-reticulocyte clinical results where we again observe evidence of a dose-proportional pharmacodynamic effect. To remind you, an F-reticulocyte is a reticulocyte containing HbF protein. While we did not observe increases in F-reticulocyte counts in the 2 mg cohort after 14 days of treatment, we observed statistically significant increases at the safety follow-up after the 14-day treatment period in both the 6 and 10 mg cohorts. FTX-6058 treatment in the 10 mg cohort demonstrated a mean 4.2-fold increase in reticulocyte counts, indicating that the persistent HbF mRNA induction is translating to HbF protein and strongly correlates with the HbF mRNA induction observed to date. As we laid out earlier, the kinetics observed across these target engagement and pharmacodynamic endpoints are consistent with the expected profile in healthy individuals. We observed maximal target engagement by day 7, HbF mRNA induction by day 14, and F-reticulocyte indicating HbF protein expression by day 21 to 24. These results demonstrate a robust relationship between target engagement, mRNA induction, and protein expression in the healthy volunteer setting. In summary, the results presented today meet the induction thresholds predicted to provide meaningful clinical benefits to sickle cell disease patients. Extensive genetic and clinical literature indicates that a two- to three-fold increase in HbF protein has the potential to translate to broad clinical benefits. We have demonstrated preclinically that HbF mRNA induction and HbF protein expression are highly correlated. These clinical results demonstrate evidence of biology and mechanism. Additionally, we predict the mean 4.5-fold induction in HbF mRNA demonstrated to date is predicted to translate to HbF protein based on the strong correlation between mRNA and protein expression observed both preclinically and clinically with HbF reticulocyte counts. If these HbF mRNA induction results continue to translate in the clinic, we believe FTX-6058 could provide clinical benefits to sickle cell patients. In terms of next steps for the program, we anticipate sharing additional results from the ongoing phase one trial at a medical conference at the end of the year, pending abstract acceptance. Based on what we've reported today, we also intend to involve sickle cell patients in a clinical trial in the fourth quarter of this year. The multiple-dose phase 1B trial would start with the 6 mg dose and include a treatment period of up to three months. It will be designed to confirm and build on our current results with an aim to demonstrate early proof of concept in individuals with sickle cell disease. We are planning that the subsequent study will be a phase 2/3 clinical trial starting in 2023. Additionally, the clinical results to date support the initiation of a clinical trial in non-sickle cell disease hemoglobinopathies, including beta thalassemia, and we intend to submit an IND by the end of this year. With that, I'll turn it back to you, Bryan.

Bryan Stuart, President and CEO

Thanks, Chris. The clinical results presented today exceeded our expectations and expand on our understanding of the preclinical data that we've generated. These results provide proof of biology and mechanism, and the increases in F-reticulocyte counts also provide the first indication that robust increases in HbF mRNA are translating to HbF protein. The opportunity to bring a new oral once-daily therapy to people living with sickle cell disease is a very exciting prospect. We believe FTX-6058 has the potential to be a significant advancement in treatment in the years ahead. These results further bolster our plans to enroll sickle cell patients in a clinical trial by the end of the year. We're very excited about the prospects for our programs in FSHD and sickle cell disease, two diseases with great unmet need, where we have shown compelling data to date. We look forward to identifying additional programs with great potential from our product engine as we seek to expand our development pipeline. We look forward to keeping you updated on our progress in the months ahead. Operator, you may now open the line for questions.

Operator, Operator

Thank you. Your first question is from Ted Tenthoff from Piper Sandler. Your line is now open.

Ted Tenthoff, Analyst

Great, thank you very much. Remarkable results. Is there any modeling what do you anticipate seeing from 20 mg, and just thinking about the differences between the healthy and sickle cell patients? Again, appreciating that we haven't seen protein yet. But is there any reason to think that this might work either better or worse in patients? Thank you so much. And congrats. It's great data.

Bryan Stuart, President and CEO

Yes, thanks Ted. I'll turn it over to Chris Morabito, and he can speak a little more to the phase 1B study and what we would anticipate seeing there.

Chris Morabito, Chief Medical Officer

So Ted, thanks for the question. The first question was about 20 mg; I assume you mean the ongoing clinical trials. Is that correct?

Ted Tenthoff, Analyst

Yes.

Chris Morabito, Chief Medical Officer

Thank you. So first, I think that if we just go by the pharmacodynamic biomarkers. I think we will not exceed the target engagement that we've achieved. We've already achieved maximal target engagement at all three doses. I don't think we'll exceed that. There might be some differences in the kinetics to reach maximum target engagement, but the limit will be exceeded. HbF mRNA induction could be increased, and again, we will likely see a difference in the kinetics to reach a maximal amount. We expect there will be an increase, but I can't predict what that number will be at this point. And similarly with F-reticulocyte counts, we expect that we will see an increase over what we currently have today, especially in terms of kinetics, so the timing of when that will happen. We are, regardless, thrilled about what we're seeing so far in the 6 to 10 mg cohorts, seeing over two to three-fold induction, which we predicted represents meaningful results. We look forward to continuing that goalpost in mind as we move forward into the phase 1B study. Your second question was about what we might expect to see in sickle cell patients versus healthy volunteers. We know from our preclinical data that we would expect to see at least the same amount of increases based on what we have seen in our preclinical models that demonstrate equally robust increases in healthy donors compared to sickle cell patients. Having said that, in human patients where the bone marrow is a bit more permissive and where RBC half-life is shorter because of the pathology of this disease, it's quite likely that we will see more significant changes, more fold induction or potentially faster induction compared to what we're seeing in healthy donors. Of course, this is the point of the 1B study that will be starting later this year, and we'll certainly be excited to share those results as they come forward.

Ted Tenthoff, Analyst

Great, excellent. Thank you guys. Congrats.

Operator, Operator

Your next question is from the line of Dae Gon Ha from Stifel. Your line is now open.

Dae Gon Ha, Analyst

Thanks for taking our questions, and congrats from me as well. But just to kind of follow up on the next plan or the patient trial phase 1B MAD study. But just wondering, given the chronic dosing that's likely from this oral administered drug, what are your thoughts on the treatment magnitude that you can expect, as you mentioned two to three-fold? Should we expect 4 to 4.5 that we saw in healthy volunteers, or can you provide more insights around that? And then the second part to that question is, given the chronic dosing, what kind of safety signals should we be expecting going forward, given that this is essentially tampering with the epigenetics? Thank you.

Bryan Stuart, President and CEO

Thanks, Dae Gon. I'll turn it over to Chris Morabito again, and you can break that question up into two answers. One is just realizing the increases that we're observing relative to the starting fetal hemoglobin levels that most sickle cell patients have. And then we can also comment on what we've observed from a safety and tolerability perspective.

Chris Morabito, Chief Medical Officer

Great, so thanks. The phase 1B trial will be our first chance to see the effects of this drug in patients. We're really excited to do that. As indicated, that will be an open-label study, so we'll be able to get relatively new feedback as we progress through the study. The goalposts for the study will be a two- to three-fold induction. Ultimately, what we want to do is get to a target percent in patients somewhere between 10% and 30%, which is where we know from genetics and other clinical data we can see potentially profound effects on patients. Patients with sickle cell disease start with roughly 5% to 10% HbF levels. Increasing by a magnitude of two to three would get them to around 10% to 30% rates, which is where we would expect to see significant clinical changes. You could potentially start to see increases even in the phase 1B, but certainly we would expect to observe this in the future phase 2 study. In terms of safety and tolerability so far, we are pleased with what we're seeing. This has been very well tolerated based on phase 1 results. As you pointed out, this is not chronic dosing, but we’re optimistic that over a longer period of administration in patients, we can achieve these kinds of results as we've seen in healthy individuals.

Dae Gon Ha, Analyst

If I can just add one more question. This may be a silly question, but these are healthy volunteers with a 4.5-fold increase. Any chance you could provide some percentage value?

Bryan Stuart, President and CEO

Dae, I'm sorry, we are having a tough time hearing you.

Operator, Operator

Yes, ma'am. I'm sorry. Sir, you might have been speaking on your speakerphone. Please pick up your handset so we can hear you clearly.

Dae Gon Ha, Analyst

Can you guys hear me now?

Bryan Stuart, President and CEO

We can. Thanks.

Dae Gon Ha, Analyst

So just a quick follow-up: The target percentage is between 10% and 30% in the patient study. But is it possible to perform a similar exercise in these healthy volunteers? Now that you've observed the four-fold increase or induction, do we get any percentage value on the HbF? Or is that completely out of the question? Thank you.

Bryan Stuart, President and CEO

Yes, Dae Gon, I would like to turn it over to Chris Moxham, and he can speak more to what we've seen preclinically in CD34 cells from both sickle cell donors as well as healthy donors.

Chris Moxham, Chief Scientific Officer

Sure, so again, what we've observed preclinically is this two to three-fold induction above baseline. In absolute terms, we have certainly seen absolute levels of HbF, as I pointed out, with upper end increases of 25% above baseline. So we've definitely been able to achieve levels that are associated with a curative effect. In the context of the healthy volunteer study, again, this is only a 21-day study—14 days of dosing within the safety follow-up period. As we highlighted, we need to overlay the normal process of erythropoiesis, which has been pointed toward detecting HbF protein in the context of reticulocytes. The question of whether we can quantify absolute levels of HbF in the context of a 21-day study is not really feasible. That would require a study of longer duration, and measuring HbF using HPLC to quantify in absolute terms is typically done in a longer duration phase 1B study.

Dae Gon Ha, Analyst

Awesome. Well, thank you very much for those responses. I'll hop back in the queue.

Operator, Operator

Next question is from the line of Joseph Schwartz from SVB Leerink. Your line is now open.

Joseph Schwartz, Analyst

Thank you very much, and congratulations from me as well. I was wondering if you have any more thoughts on why you saw greater efficacy in healthy volunteers than the two to three-fold increases in mRNA you expected based on your preclinical work? Do you think that's purely due to greater exposure due to a longer half-life than expected? Are there any other factors in your view that might have contributed?

Bryan Stuart, President and CEO

Sure, that's a very good question. We don't have any clear indicators as to why today. A notable difference perhaps between the preclinical data, again, where we showed very robust two to three-fold increases in HbF. In, for example, in the Townes mouse model system, which again is humanized in the context of the globin genes, but still operating under the control of the murine transcription factors. Now, we're going to a fully humanized system in the healthy volunteer context, and that may account for some differences in the level of fold induction that have exceeded the levels we observed in the preclinical study. We are certainly very pleased with these results. Again, we remain focused on a two to three-fold induction to provide meaningful clinical benefit and certainly look to see whether this translates now into the sickle cell setting. As Chris Morabito implied, we believe the sickle cell setting is even more permissive, given that we know erythropoiesis is elevated, baseline HbF levels are elevated, and that red blood cells have a shorter half-life in the sickle cell setting. This whole context gives us a greater opportunity to see even significant induction.

Joseph Schwartz, Analyst

That's very interesting. And then, I recall that FTX-6058 has been developed to have high pan-cellularity. I was wondering if you could talk about whether you have been able to evaluate that attribute in healthy volunteers and what the implications are for when you get into patients?

Bryan Stuart, President and CEO

Yes, and I'll turn it over to Chris. He can remind you what we did observe preclinically and then what we expect here.

Chris Morabito, Chief Medical Officer

Yes. So again, preclinically, what we did observe is a very robust pan-cellular induction where approximately 90% of the cells were demonstrated to be expressing very high levels of HbF protein. In the context of the healthy volunteer study, we are unable to assess that. It would really be in the context of the sickle cell study where we would have a greater chance to collect data that could speak to pan-cellular induction. But certainly, again, based on the preclinical data, either in healthy volunteer cells derived from healthy donors or CD34 cells obtained from sickle cell donors, we see a very consistent two to three-fold induction and a very consistent pan-cellular induction in either setting.

Joseph Schwartz, Analyst

And then, if I could just ask the bigger picture question. What do you think are the implications of this work on the broader Fulcrum Seek platform? Are there other particular programs in your development pipeline where there might be more direct read-through than others based on any similarities in the biology or your approach to modulate gene expression in a congruent way?

Bryan Stuart, President and CEO

Thanks, Joe. Broadly, obviously, we're very enthusiastic, both about this data and the FSHD data in terms of validating Fulcrum Seek and our approach. Both of these programs, as we talked about, came out of the Fulcrum Seek engine. We utilized our own medicinal chemistry to create this compound that we're very excited about in the FTX-6058 program, and for the other FSHD, we identified a target that had chemical matter that we were able to license. We feel like this is great validation. We're very excited with FTX-6058 to be taking that into other select hemoglobinopathies as we referenced. We also feel like it presents great opportunity. Additionally, I would say hematology remains an important area of focus for Fulcrum Seek, and the type of commitment and expertise we are building is expected to lead to other programs as well.

Joseph Schwartz, Analyst

Great. Well, congrats. Thank you.

Operator, Operator

Your next question is from Matthew Harrison from Morgan Stanley. Your line is now open.

Matthew Harrison, Analyst

Good morning. I guess a couple of things I want to touch on. So I know others have asked about higher doses and dose range. It just wasn't clear to me. Could you expand? Is your expectation to look at a wider dose range, or do you feel comfortable with 10 mg and going into the next study? And then secondly, I want to ask about cumulative change or aggregate change. Would you expect in sickle cell patients being dosed over a longer period of time for these improvements to become larger than what you've seen in these healthier volunteers?

Bryan Stuart, President and CEO

Thanks, Matthew. I'll turn it over to Chris, and we can discuss how we're thinking about dosing in the phase 1B as well as address your second question regarding cumulative changes.

Chris Morabito, Chief Medical Officer

As I said, the first dose for the upcoming phase 1B study will be 6 mg, and we intend to dose upward for a period of up to three months in an open-label way. At 6 mg, we haven't yet determined the second dose for the study. It could be 10 mg based on the data that we reviewed today; it may be 20 mg based on the data that will come in from the healthy volunteer study that is still running. We aim to select two doses that will yield informative ranges in the phase 1B study, which will allow us to choose one dose for the potentially pivotal phase 2 study. Therefore, a broad range of doses in the 1B study will generate PK and PD responses that can help build a robust model to select the optimal dose. We can’t yet comment on what the upper dose will be, but that's the approach we will take as we move that study forward. We will make the dose determination as we get closer to trial initiation. Regarding the magnitude of changes: again, we stick to what we've been saying; our goalposts here would be a two- to three-fold increase in sickle cell patients at whichever doses we test in the phase 1B study. Of course, we would be thrilled to see increases over that, especially in terms of HbF protein levels. But as I have mentioned before, and both Chris and Bryan reiterated, a two- to three-fold increase would be transformational, particularly with an oral medicine.

Operator, Operator

Your next question is from Tazeen Ahmad from Bank of America. Your line is now open.

Tazeen Ahmad, Analyst

Okay, good morning. I think that's me. Hi, guys. Just wanted to ask a couple of questions for points of clarification. So, just so that I'm clear, when should we expect to see a report of the results of increases in HbF protein?

Bryan Stuart, President and CEO

We plan to begin enrollment in the Phase 1B trial in the fourth quarter of this year. And we plan on providing an update in the second quarter of next year.

Tazeen Ahmad, Analyst

And then, how long from the time you start treating patients would you expect to start to see the impact on HbF? Is this something that would be immediate, or would it take a certain level of time?

Bryan Stuart, President and CEO

Yes, as we discussed, as outlined in the slide, the first time you would expect to see quantifiable HbF protein in patients would be around a month, and after three months, we would be much more likely to see that. It just takes longer for the HbF to be quantifiable in the periphery.

Tazeen Ahmad, Analyst

And are patients uniformly responsive, or is there variability?

Bryan Stuart, President and CEO

Go ahead, Chris.

Chris Morabito, Chief Medical Officer

Yes, to that question, what we've seen preclinically is that all the donors we have tested so far have shown a very robust increase in HbF levels after treatment with FTX-6058, whether derived from a healthy donor or sickle cell donor, or even that donor with the sickle cell trait. This contrasts with hydroxyurea, which has a much more varied response and frankly weaker efficacy based on our preclinical data. So we are very encouraged by the fact that we see a robust and significant increase in HbF protein levels after treatment with FTX-6058.

Tazeen Ahmad, Analyst

And then last question for me based on that: would you expect that the entire sickle cell population would be eligible or would there be certain criteria at least for trial enrollment?

Bryan Stuart, President and CEO

Yes, the entire population would be eligible for this. Absolutely.

Operator, Operator

Your last question is from the line of Judah Frommer from Credit Suisse. Your line is now open.

Judah Frommer, Analyst

Thanks for the question. Just one on the potential regulatory path forward. I think in the past, you've referenced a competitor's bar of 3% improvement in HbF protein. I mean, the results today seem to indicate that you should be or could be well above that. So any thoughts on that bar and any conversations with the agency that may help you move forward on either a biomarker or another perspective?

Bryan Stuart, President and CEO

I would say in terms of the bar is, as you referenced, there is a very clear understanding from human genetics, from these patients who have hereditary persistence of fetal hemoglobin that even small increases, referenced as a percentage of fetal hemoglobin, can have very meaningful impacts on patients. Obviously, greater increases in fetal hemoglobin have an even greater impact, up to the point where they are essentially asymptomatic. What we've observed, relative to that 3%, which would be about a little over a one-fold increase, is that we are observing significantly greater increases. We are very enthusiastic about that. Our goal, right now, as Chris Morabito mentioned, is to get into a phase 1B trial, be able to select a dose and then hopefully into a phase 2/3 registration trial to bring this to patients as quickly as possible.

Judah Frommer, Analyst

Great, thanks.

Operator, Operator

There are no further questions. And with that, this concludes today's conference call. Thank you for attending. You may now disconnect. Have a great day.

Christi Waarich, Director of Investor Relations and Corporate Communications

Goodbye.